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Updated: Jun 13, 2025
Seven Steps to Stellate Cells
Published on: May 10, 2011
Wedelolactone Attenuates Liver Fibrosis and Hepatic Stellate Cell Activation by Suppressing the Hippo Pathway
Wei Zhang1,2, Kai Gao1, Ya Bai1
1Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Insights
Wedelolactone (WED) alleviates liver fibrosis by inhibiting the Hippo pathway, specifically targeting Yes-associated protein (YAP) and tafazzin (TAZ). This natural compound suppresses hepatic stellate cell activation, offering a potential therapeutic strategy for chronic liver diseases.
Area of Science:
- Hepatology
- Molecular Biology
- Pharmacology
Background:
- Liver fibrosis is a critical stage in chronic liver disease progression.
- The Hippo pathway, involving Yes-associated protein (YAP) and tafazzin (TAZ), plays a key role in liver fibrosis pathogenesis.
- Wedelolactone (WED) shows anti-fibrotic effects, but its molecular targets and mechanisms are unclear.
Purpose of the Study:
- To elucidate the molecular targets and mechanisms of wedelolactone (WED) in alleviating liver fibrosis.
- To investigate the role of the Hippo pathway, specifically YAP and TAZ, in WED's anti-fibrotic action.
Main Methods:
- In vitro models using hepatic stellate cells (HSCs) stimulated with transforming growth factor-beta 1 (TGF-β1).
- Assessed WED's effects on HSC activation markers (α-smooth muscle actin) and Hippo pathway components (YAP, TAZ) at mRNA and protein levels.
- Utilized molecular docking (MD) and cellular thermal shift assay (CETSA) to confirm allosteric regulation of YAP by WED.
- Investigated the impact of YAP knockdown or inhibition on WED's efficacy.
Main Results:
- WED significantly reduced liver fibrosis and injury by inhibiting YAP and TAZ expression.
- WED suppressed TGF-β1-induced HSC activation and expression of α-SMA, YAP, and TAZ.
- Allosteric regulation of YAP by WED was confirmed through molecular docking and CETSA.
- Specific inhibition of YAP did not enhance WED's suppressive effects on HSC activation.
Conclusions:
- Wedelolactone (WED) effectively alleviates liver fibrosis by suppressing the Hippo/YAP/TAZ signaling pathway.
- YAP activity is potentially regulated by WED through allosteric mechanisms.
- WED represents a promising therapeutic agent for liver fibrosis targeting the Hippo pathway.
Abstract:
Liver fibrosis is a commonly observed pathological phenomenon that occurs during the progression of various types of chronic liver diseases. The Hippo pathway is closely associated with the pathogenesis of liver fibrosis. Previous studies have shown that wedelolactone (WED) has a significant antihepatic fibrosis effect, whereas the target and mechanism underlying WED remain elusive. In this study, we found that WED significantly alleviated liver fibrosis and injury by inhibiting the expression of Yes-associated protein (YAP) and tafazzin (TAZ). In an in vitro model, WED suppressed the activation of hepatic stellate cells (HSCs) induced by transforming growth factor (TGF-β1), as well as the mRNA and protein expression of α-smooth muscle actin (α-SMA), YAP, and TAZ. The allosteric regulation of YAP by WED was confirmed using MD and cellular thermal shift assay. Moreover, specific knockdown or inhibition of YAP did not enhance the suppressive effect of WED on HSC activation or protein expression associated with fibrosis. These findings demonstrated that the administration of WED effectively alleviated liver fibrosis by suppressing the Hippo/YAP/TAZ pathways. In addition, YAP activity may be regulated by WED via allosteric regulation.
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